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May 2011

Volume 140Issue 6p1701-1846
Inflammatory Bowel Disease: An Update on Fundamental Biology and Clinical Management

Introduction

  • Inflammatory Bowel Disease: An Update on the Fundamental Biology and Clinical Management

    • Richard Blumberg,
    • Judy Cho,
    • James Lewis,
    • Gary Wu
    Published in issue: May 2011
    p1701-1703
    The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), affect approximately 1–2 of every 1000 people in developed countries. These chronic diseases result in significant morbidity and mortality. Quality of life and life expectancy are compromised. While there is no cure for these diseases, the last two decades have been a period of major advances in our understanding of the biology of intestinal inflammation and how it is related to IBD. This in turn has led to the development and refinement of several new treatment strategies.
  • Recent Insights Into the Genetics of Inflammatory Bowel Disease

    • Judy H. Cho,
    • Steven R. Brant
    Published in issue: May 2011
    p1704-1712.e2
    Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemiologic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL.
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  • Development of the Human Gastrointestinal Microbiota and Insights From High-Throughput Sequencing

    • Maria Gloria Dominguez-Bello,
    • Martin J. Blaser,
    • Ruth E. Ley,
    • Rob Knight
    Published in issue: May 2011
    p1713-1719
    Little was known about the development of the gastrointestinal (GI) tract microbiota, until recently, because of difficulties in obtaining sufficient sequence information from enough people or time points. Now, with decreased costs of DNA sequencing and improved bioinformatic tools, we can compare GI tract bacterial communities among individuals, of all ages from infancy to adulthood. Some key recent findings are that the initial bacterial community, even in the GI tract, depends strongly on delivery mode; that the process of early development of the microbiota is highly unstable and idiosyncratic; that the microbiota differs considerably among children from different countries; and that older adults have substantially different GI tract communities than younger adults, indicating that the GI tract microbiota can change throughout life.
  • The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases

    • Benoit Chassaing,
    • Arlette Darfeuille–Michaud
    Published in issue: May 2011
    p1720-1728.e3
    Intestinal inflammation arises from abnormal host–microbe interactions. The perturbations of homeostatic coexistence involve host genetic factors, barrier function, innate and adaptive immunity, as well as qualitative and quantitative changes in the composition of the microbiota. Dysbiosis toward selected micro-organisms and decreased complexity of commensal bacteria have been observed in patients with Crohn's disease and ulcerative colitis, but it is not clear whether the dysbiosis contributes to development of inflammatory bowel disease or is instead a consequence of the disease.
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  • Interactions Between the Host Innate Immune System and Microbes in Inflammatory Bowel Disease

    • Clara Abraham,
    • Ruslan Medzhitov
    Published in issue: May 2011
    p1729-1737
    The intestinal immune system defends against pathogens and entry of excessive intestinal microbes; simultaneously, a state of immune tolerance to resident intestinal microbes must be maintained. Perturbation of this balance is associated with intestinal inflammation in various mouse models and is thought to predispose humans to inflammatory bowel disease (IBD). The innate immune system senses microbes; dendritic cells, macrophages, and epithelial cells produce an initial, rapid response. The immune system continuously monitors resident microbiota and utilizes constitutive antimicrobial mechanisms to maintain immune homeostasis.
  • Autophagy, Microbial Sensing, Endoplasmic Reticulum Stress, and Epithelial Function in Inflammatory Bowel Disease

    • Arthur Kaser,
    • Richard S. Blumberg
    Published in issue: May 2011
    p1738-1747.e2
    Increasing evidence has emerged that supports an important intersection between 3 fundamental cell biologic pathways in the pathogenesis of inflammatory bowel disease. These include the intersection between autophagy, as revealed by the original identification of ATG16L1 and IRGM as major genetic risk factors for Crohn's disease, and intracellular bacterial sensing, as shown by the importance of NOD2 in autophagy induction upon bacterial entry into the cell. A pathway closely linked to autophagy and innate immunity is the unfolded protein response, initiated by endoplasmic reticulum stress due to the accumulation of misfolded proteins, which is genetically related to ulcerative colitis and Crohn's disease (XBP1 and ORMDL3).
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  • Hypoxia and Metabolic Factors That Influence Inflammatory Bowel Disease Pathogenesis

    • Louise E. Glover,
    • Sean P. Colgan
    Published in issue: May 2011
    p1748-1755
    The gastrointestinal epithelium is anatomically positioned to provide a selective barrier between the anaerobic lumen and lamina propria, which has a high rate of metabolism. Supported by a complex vasculature, this important barrier is affected by reduced blood flow and resultant tissue hypoxia, particularly during the severe metabolic shifts associated with active inflammation in individuals with inflammatory bowel disease. Activation of hypoxia-inducible factor (HIF) under these conditions promotes resolution of inflammation in mouse models of disease.
  • Proinflammatory Cytokines in the Pathogenesis of Inflammatory Bowel Diseases

    • Warren Strober,
    • Ivan J. Fuss
    Published in issue: May 2011
    p1756-1767.e1
    The cytokine responses characterizing the inflammatory bowel diseases are the key pathophysiologic elements that govern the initiation, evolution, and, ultimately, the resolution of these forms of inflammation. Studies during the last 2 decades now provide a detailed (but not yet complete) picture of the nature of these responses. The first tier of cytokine responses are governed by the T-cell differentiation patterns dominating the disease. In Crohn's disease, the major cytokines arise from T-helper cell (Th) 1 and Th17 CD4+ T-cell differentiation and consist of interferon-γ and interleukin (IL)-17/IL-22 generated by these types of differentiation.
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  • Regulation of Homeostasis and Inflammation in the Intestine

    • Thomas T. MacDonald,
    • Ivan Monteleone,
    • Massimo Claudio Fantini,
    • Giovanni Monteleone
    Published in issue: May 2011
    p1768-1775
    The gastrointestinal tract is the largest immune interface with the environment. Exposure to large numbers of dietary and microbial antigens requires complex and highly regulated immune responses by different mucosal cell types, which result in the induction and maintenance of intestinal homeostasis. Defects in this equilibrium can disrupt the homeostatic mechanisms and lead to chronic intestinal inflammation. We review the cell populations and mechanisms involved in the control of intestinal homeostasis and inflammation, focusing on inflammatory bowel diseases.
  • Blocking Lymphocyte Localization to the Gastrointestinal Mucosa as a Therapeutic Strategy for Inflammatory Bowel Diseases

    • Eduardo J. Villablanca,
    • Barbara Cassani,
    • Ulrich H. von Andrian,
    • J. Rodrigo Mora
    Published in issue: May 2011
    p1776-1784.e5
    Lymphocyte migration (homing) to specific tissues has an important role during protective and pathological immune responses, including inflammatory bowel diseases. Lymphocytes use integrin α4β7 and the chemokine receptor CCR9 to localize to the gastrointestinal mucosa; their respective ligands, mucosal addressin cell adhesion molecule-1 and CCL25, are displayed on endothelial cells in intestinal postcapillary venules. Although gastrointestinal-homing receptors are required for lymphocyte migration to the intestine in the noninflamed steady state, their role during inflammation is a matter of debate.
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  • Epidemiology and Natural History of Inflammatory Bowel Diseases

    • Jacques Cosnes,
    • Corinne Gower–Rousseau,
    • Philippe Seksik,
    • Antoine Cortot
    Published in issue: May 2011
    p1785-1794.e4
    In the West, the incidence and prevalence of inflammatory bowel diseases has increased in the past 50 years, up to 8–14/100,000 and 120–200/100,000 persons, respectively, for ulcerative colitis (UC) and 6–15/100,000 and 50–200/100,000 persons, respectively, for Crohn's disease (CD). Studies of migrant populations and populations of developing countries demonstrated a recent, slow increase in the incidence of UC, whereas that of CD remained low, but CD incidence eventually increased to the level of UC.
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  • New Concepts in Intestinal Imaging for Inflammatory Bowel Diseases

    • Joel G. Fletcher,
    • Jeff L. Fidler,
    • David H. Bruining,
    • James E. Huprich
    Published in issue: May 2011
    p1795-1806.e7
    In the last decade, multiple imaging technologies have been developed that improve visualization of the mucosal, mural, and perienteric inflammation associated with inflammatory bowel diseases. Whereas these technologies have traditionally been used to detect and stage suspected enteric inflammation, we review new, emerging roles in detecting clinically occult inflammation (in asymptomatic patients) and inflammatory complications, predicting response prior to therapy, assessing response after therapy, and enteric healing.
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  • Intestinal Inflammation and Cancer

    • Thomas A. Ullman,
    • Steven H. Itzkowitz
    Published in issue: May 2011
    p1807-1816.e1
    Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer (CRC). Chronic inflammation is believed to promote carcinogenesis. The risk for colon cancer increases with the duration and anatomic extent of colitis and presence of other inflammatory disorders (such as primary sclerosing cholangitis), whereas it decreases when patients take drugs to reduce inflammation (such as mesalamine and steroids). The genetic features that lead to sporadic CRC—chromosome instability, microsatellite instability, and DNA hypermethylation—also occur in colitis-associated CRC.
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  • The Utility of Biomarkers in the Diagnosis and Therapy of Inflammatory Bowel Disease

    • James D. Lewis
    Published in issue: May 2011
    p1817-1826.e2
    Fecal and serologic biomarkers can be used in the diagnosis and management of inflammatory bowel disease (IBD). Fecal markers such as calprotectin and lactoferrin have been studied for their ability to identify patients with IBD, assess disease activity, and predict relapse. Antibodies against Saccharomyces cerevisiae and perinuclear antineutrophil cytoplasmic proteins have been used in diagnosis of IBD, to distinguish Crohn's disease (CD) from ulcerative colitis, and to predict the risk of complications of CD.
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  • Conventional Medical Management of Inflammatory Bowel Disease

    • Daniel Burger,
    • Simon Travis
    Published in issue: May 2011
    p1827-1837.e2
    Conventional therapies for ulcerative colitis and Crohn's disease (CD) include aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti–tumor necrosis factor agents. A time-structured approach is required for appropriate management. Traditional step-up therapy has been partly replaced during the last decade by potent drugs and top-down therapies, with an accelerated step-up approach being the most appropriate in the majority of patients. When patients are diagnosed with CD or ulcerative colitis, physicians should consider the probable pattern of disease progression so that effective therapy is not delayed.
    Online ExtraAdditional Online Content Available
  • Future Therapeutic Approaches for Inflammatory Bowel Diseases

    • Scott E. Plevy,
    • Stephan R. Targan
    Published in issue: May 2011
    p1838-1846
    In this review, we speculate about future therapeutic approaches for inflammatory bowel diseases (IBDs), focusing on the need for better preclinical and clinical models and approaches beyond small molecules and systemically administered biologics. We offer ideas to change clinical trial programs and to use immunologic and genetic biomarkers to personalize medicine. We attempt to reconcile past therapeutic successes and failures to improve future approaches. Some of our ideas might be provocative, but we hope that the examples we provide will stimulate discussion about what will advance the field of IBD therapy.

Frontmatter

  • Cover 1

    Published in issue: May 2011
    OFC
  • Editorial Board

    Published in issue: May 2011
    A2
  • Table of Contents

    Published in issue: May 2011
    A5-A6
  • Information for Authors and Readers

    Published in issue: May 2011
    A9-A10
    Gastroenterology is the premiere journal in the field of gastrointestinal disease and is led by an internationally renowned board of editors. As the official journal of the AGA Institute, Gastroenterology delivers up-to-date and authoritative coverage of both basic and clinical gastroenterology and hepatology. Regular features include research and perspectives by leading authorities, reports on the latest technologies for diagnosing and treating digestive diseases, images illustrating important clinical findings, reviews of scholarly media, medical news, meeting summaries, video abstracts, and monthly podcasts.
  • Copyright Assignment, Authorship Responsibility, NIH Funding, Financial Disclosure, Institutional Review Board/Animal Care Committee Approval, and Sponsorship

    Published in issue: May 2011
    A18
    Copyright Assignment. In consideration of the American Gastroenterological Association (AGA) Institute (the “AGA Institute”) taking action to review and credit the below-identified submission (the “Manuscript”), and for other valuable consideration, the receipt and sufficiency of which is hereby acknowledged, the undersigned authors and/or creators (the “Authors”), jointly and severally, hereby transfer, convey, and assign to the AGA Institute, free and clear of any liens, licenses or encumbrances, the entire right, title, and interest in and to the Manuscript throughout the world, including without limitation in and to any and all copyrights for the Manuscript (including but not limited to rights to copy, publish, excerpt, collect royalties and make derivative works) in print, electronic, Internet, broadcast, and all other forms and media now or hereafter known, and for any and all causes of action heretofore accrued in Authors' favor for infringement of the aforesaid copyrights, to have and to hold the same unto the AGA Institute, its successors and assigns, for and during the existence of the aforesaid copyrights, and all renewals and extensions thereof.
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